Spontaneous immune responses in
cancer patients have been described. Yet their clinical relevance and the conditions for their generation remain unclear. We characterized conditions that determine immune responses in primary
breast cancer patients. We used tetramer analysis, ex vivo IFN-gamma ELISPOT, cytotoxicity assays, and ELISA in 207 untreated patients and 12 Her-2/neu-specific CD8 T-cell lines to evaluate
tumor-specific T cells (TC) in the bone marrow or MUC1-specific
antibodies in the blood. Multiplex analysis was performed to quantify 27 intratumoral
cytokines,
chemokines, and
growth factors. Results were compared with multiple pathologic and clinical parameters of the patients and
tumors. Forty percent of the patients showed
tumor-specific TC responses. These correlated with
tumors of high differentiation,
estrogen receptor expression, and low proliferative activity, and with a reduced
cancer mortality risk. High
tumor cell differentiation correlated with increased intratumoral, but not plasma, concentrations of IFN-alpha and reduced
transforming growth factor (TGF)beta1. In an in vitro priming experiment these two
cytokines increased or inhibited, respectively, the capacity of dendritic cells to induce
tumor-reactive TC.
Tumor-specific B-cell responses, mainly of
IgM isotype, were detectable in 50% of the patients and correlated with advanced
tumor stage, increased TGFbeta1, reduced IFN-alpha, and absence of TC responses. We show here that different types of immune responses are linked to distinct
cytokine microenvironments and correlate with prognosis-relevant differences in
tumor pathobiology. These findings shed light on the relation between immune response and
cancer prognosis.